Similarities and Differences between Multisystem Inflammatory Syndrome in Children (MIS-C) and Kawasaki Disease Shock Syndrome

This study aimed to investigate the characteristics of COVID-19-associated multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease shock syndrome (KDSS) and to compare the similarities and differences between the two diseases. The incidence of KDSS and MIS-C was also estimated. Medical records of patients diagnosed with MIS-C or KDSS at four hospitals from January 2013 to December 2022 were retrospectively reviewed. Thirty-one patients were enrolled in the study in either an MIS-C group (n = 22) or a KDSS group (n = 9). The incidence of KDSS in KD was 0.8% (9/1095) and the incidence of MIS-C versus KD was 10.2% (22/216). Compared with the MIS-C group, the KDSS group had longer hospital stays and more severe systemic inflammation (e.g., anemia, elevated C-reactive protein, hypoalbuminemia, and pyuria) and organ dysfunction (e.g., number of involved organs, shock, vasoactive infusion, and intensive care unit admission). All patients in the MIS-C group, but none in the KDSS group, including two patients during the COVID-19 pandemic, had laboratory evidence of SARS-CoV-2 infection. MIS-C and KDSS shared demographic, clinical, and laboratory characteristics; organ dysfunction; treatment; and outcomes. Overall severity was more severe in patients with KDSS than in those with MIS-C. The most important difference between MIS-C and KDSS was whether SARS-CoV-2 was identified as an infectious trigger.


Introduction
Most children with COVID-19, which is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are asymptomatic or have mild symptoms [1,2].However, in April 2020, Verdoni et al. [3] reported an outbreak in Italian children presenting with a severe systemic inflammatory disease resembling Kawasaki disease (KD) who often required admission to an intensive care unit (ICU) due to cardiac dysfunction and shock.Soon after, similar cases began to be reported in the United Kingdom, Spain, France, the Children 2023, 10, 1527 2 of 12 United States, India, Brazil, and many other countries, including Korea [2,4].The condition is now called COVID-19-associated multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome temporarily related to SARS-CoV-2 (PIMS-TS) [4][5][6].MIS-C is a serious complication that can occur two to eight weeks after SARS-CoV-2 infection and is characterized by infectious triggers, systemic inflammation, and organ dysfunction [7].The presence of "KD-like features" in patients with MIS-C has received clinical attention, but the extent of organ dysfunction in patients with MIS-C is of greater importance as it directly affects the disease course and outcome [8][9][10].
Organ dysfunction, including shock, is also seen in a unique and severe form of KD called Kawasaki disease shock syndrome (KDSS) [11,12].The incidence of KDSS ranges from 1% to 7% in patients with KD [13].Like MIS-C, KDSS has a relatively short history [14].The term was coined in 2009 by Kanegaye et al. [15] to differentiate this severe form from hemodynamically stable KD.In fact, KDSS is distinct in various aspects [16][17][18].Coronary artery abnormalities (CAAs) and intravenous immunoglobulin (IVIG) resistance, a major concern in the field of KD research, are more common in KDSS than in hemodynamically stable KD [12].KDSS also has severe manifestations in terms of systemic inflammation (e.g., cytopenia, elevated C-reactive protein [CRP], or hypoalbuminemia) and organ dysfunction (e.g., cardiac, gastrointestinal, or neurologic manifestations); all features are encountered in MIS-C [17].Because MIS-C and KD share KD-like features, many studies have been conducted to elucidate the relationship between MIS-C and KD [8,9].Few studies have addressed the relationship between MIS-C and KDSS [10,14], even though MIS-C and KDSS share organ dysfunction in addition to KD-like features.
In this study, we investigated the characteristics of patients diagnosed with MIS-C or KDSS and compared the similarities and differences.We also estimated the incidence of KDSS and MIS-C in Korea, which had not previously been reported.

Study Design and Population
This was a multicenter retrospective study of patients who were hospitalized with MIS-C or KDSS between January 2013 and December 2022, at the Departments of Pediatrics of four hospitals in Korea: Seoul St. Mary's Hospital, Eunpyeong St. Mary's Hospital, Bucheon St. Mary's Hospital, and Daejeon St. Mary's Hospital.All data were collected through the Clinical Data Warehouse (CDW), which incorporates affiliated hospitals under the Catholic Medical Center in Korea.The CDW collects and distributes clinical data to researchers, including more than 15 million anonymized electronic medical records, following a comprehensive ethical board review [19].
The present study population was selected from the CDW.Patients who had a diagnosis code for MIS-C (U10.9) and met the MIS-C case definition [7] were assigned to the MIS-C group.Among patients with KD (M30.3),those who received vasoactive drugs or had a secondary diagnosis code for hypotension (I95.9) were allocated to the KDSS group.The study protocol was approved by the Institutional Review Board of The Catholic University of Korea (approval number: HC23WIDI0040), and the need for informed consent was waived due to the study's retrospective nature.A diagnosis of KD is based on the American Heart Association criteria [20,21].Complete KD was diagnosed by the presence of fever and ≥4 of 5 KD-like features: rash, conjunctivitis, oropharyngeal inflammation, extremity changes, and cervical lymphadenopathy.

MIS
Incomplete KD was indicated by the presence of fever and <4 of 5 KD-like features plus compatible laboratory or echocardiographic features.Patients who also had shock or hypotension (systolic hypotension for age, a decrease in systolic blood pressure from baseline ≥ 20%, or clinical signs of hypoperfusion) were diagnosed with KDSS [15,16].
As assessment of IVIG resistance or initial treatment failure was made when patients with MIS-C or KDSS received second-line treatment due to persistent fever ≥ 36 h after completion of initial treatment (IVIG ± systemic steroids) [22].A diagnosis of CAA was based on the z-score classification system recommended in the American Heart Association guidelines: a z-score for coronary artery size ≥ 2.0 indicated a coronary artery dilatation and a z-score for coronary artery size ≥ 2.5 indicated a coronary artery aneurysm [20].
Microbiological results were recorded, including bacterial or viral cultures, serology, and polymerase chain reaction (PCR) analysis.For patients with MIS-C, the date of COVID-19 diagnosis before hospitalization and the results of SARS-CoV-2 PCR tests, SARS-CoV-2-specific antigen, and SARS-CoV-2-specific antibodies during hospitalization were investigated separately.When calculating the incidence of KDSS and MIS-C, KD patients who received treatment with IVIG (2 g/kg/dose) and aspirin (30-50 mg/kg/day) during hospitalization were included in the number of KD patients.

Statistical Analysis
Data for categorical variables are presented as frequencies and percentages, while continuous variables are displayed as medians and ranges.For statistical analysis, Fisher's exact test was used to compare categorical variables and the Mann-Whitney U test was used to compare continuous variables.All tests were two-tailed, and a p-value < 0.05 was considered statistically significant.Statistical analyses were performed using IBM SPSS Statistics software Version 24.0 (IBM Corporation, Armonk, NY, USA).

Incidence of KDSS and MIS-C
Thirty-one patients were enrolled in this study; twenty-two met the case definition of MIS-C and nine met the definition of KDSS.The study period was divided into the "pre-COVID-19 pandemic" (January 2013 to December 2019) and the "COVID-19 pandemic" (January 2020 to December 2022).The total number of KD patients was 1095: 879 (125 per year) during the pre-COVID-19 pandemic and 216 (72 per year) during the COVID-19 pandemic.
Comparing the demographic and clinical characteristics of the two groups, the KDSS group had a longer hospital stay than the MIS-C group (p = 0.007), and there were no significant differences in other variables (Table 1).
Comparing the demographic and clinical characteristics of the two groups, the KDSS group had a longer hospital stay than the MIS-C group (p = 0.007), and there were no significant differences in other variables (Table 1).
Table 2 shows the laboratory characteristics of the two groups.In comparison with the MIS-C group, the KDSS group exhibited significantly lower median values of hemoglobin (p = 0.007) and albumin (p = 0.011), along with a higher median value of CRP (p = 0.022).Moreover, pyuria was more prevalent in the KDSS group than in the MIS-C group (p = 0.006).The KDSS group also exhibited higher median values of WBC count, ESR, AST, ALT, NT-proBNP, and ferritin, along with lower median values of ALC and platelet count compared with the MIS-C group (p > 0.05).Coagulopathy was more prevalent in the KDSS group than in the MIS-C group, but abnormal TG or fibrinogen and meeting the 2016 MAS criteria were more common in the MIS-C group than in the KDSS group (p > 0.05).
Table 3 presents the four components of the CSTE/CDC definition and demonstrates their applicability to the MIS-C and KDSS groups.In both groups, all patients were febrile children or adolescents aged <21 years, had systemic inflammation (CRP ≥ 3.0 mg/dL), Children 2023, 10, 1527 6 of 12 and showed two or more organ-dysfunction events.In a comparison of organ dysfunction between the two groups, the median number of organs involved was higher in the KDSS group than in the MIS-C group (p = 0.040), as was the frequency of shock (p < 0.001).All patients in the MIS-C group, but none in the KDSS group, had laboratory evidence of SARS-CoV-2 infection (p < 0.001).Of the nine patients in the KDSS group, seven were hospitalized during the pre-COVID-19 pandemic and two were hospitalized during the pandemic but had no history of recent SARS-CoV-2 infection and tested negative for SARS-CoV-2 PCR, SARS-CoV-2-specific antigen, and SARS-CoV-2-specific antibodies during hospitalization.
Table 3. CSTE/CDC case definition [7] and its application to the two groups.
Empirical antibiotics were administered to 28 patients (87.1%) and vasoactive drugs were given to 13 (41.9%).ICU admission was required in 14 (45.2%) and CAAs were observed in 9 (29.0%).Notably, all 31 patients in both groups recovered successfully.Comparing the treatment and outcomes between the two groups, the frequencies of vasoactive infusion (p = 0.001) and ICU admission (p < 0.001) were higher in the KDSS group than in the MIS-C group.Comparisons of other variables of treatment and outcomes revealed no statistical differences (Table 4).

Discussion
In this study, the incidence of KDSS in KD was 0.8% and the incidence of MIS-C versus KD was 10.2%.All 31 patients included in the MIS-C and KDSS groups presented with KD-like features, systemic inflammation, and organ dysfunction.The severity of systemic inflammation and the extent of organ dysfunction were more pronounced in the KDSS group than in the MIS-C group.All in the MIS-C group had laboratory evidence of SARS-CoV-2 infection, but none in the KDSS group.
Common presentations of MIS-C include prolonged fever, KD-like features, gastrointestinal symptoms, shock, or coagulopathy [1][2][3].Many of these features are also encountered in cases of acute abdomen, toxic shock syndrome (TSS), septic shock, or multiorgan dysfunction syndrome (MODS), which sometimes causes diagnostic confusion in clinical practice [12,14].In the first case report of MIS-C in Korea [24], the patient showed abdominal pain, shock, and heart failure without KD-like features and was initially considered to have septic shock of gastrointestinal origin.Conjunctivitis and oropharyngeal inflammation appeared on the sixth day of hospitalization.Because KD-like features may not be present in the acute phase of MIS-C, and one-quarter of patients with MIS-C do not develop KD-like features throughout their disease [25,26], MIS-C should be suspected in patients presenting with unknown etiology of shock, heart failure, or gastrointestinal symptoms, even in the absence of KD-like features [10,27].
Although KDSS is a subtype of KD, the two are significantly different [11,12].In KDSS, systemic inflammatory markers, such as anemia, thrombocytopenia, CRP elevation, hypoalbuminemia, or hyperferritinemia, are more frequent and more severe compared with KD [15].While some patients with KD may develop rare complications of gastrointestinal, neurologic, or musculoskeletal manifestations, KDSS is characterized by the presence of multi-organ dysfunction, including cardiac, gastrointestinal, hematologic, neurologic, renal, and musculoskeletal manifestations [16].Epidemiologically, KDSS also shows distinct characteristics [17].Compared with KD patients, those with KDSS have a higher median age, and KDSS is more common in non-Asian regions and includes a larger Hispanic population [13,14].Based on these differences, it had been suggested that KDSS should be classified as a distinct disease entity from KD [15].As with MIS-C, KDSS often presents with gastrointestinal symptoms with severe inflammation, and it can be mistaken as acute abdomen, TSS, septic shock, or MODS [11,12].KDSS and MIS-C may present a variety of clinical manifestations, and delayed recognition of the disease can result in a fatal outcome [14,18].
Table 5 compares the important characteristics of MIS-C, KDSS, and KD, utilizing data from a United States study on MIS-C (n = 186) [26], a literature review on KDSS (n = 103) [13], and a Korean nationwide survey on KD (n = 14,916) [28].Unlike KD, both MIS-C and KDSS predominantly affect patients older than five years [18].Whereas KD is frequent in East Asia (Japan, Korea, and Taiwan), both MIS-C and KDSS are relatively frequent in Europe and North America (Hispanic and black populations) and rare in East Asia (Asian populations) [17].All three diseases present with systemic inflammation and organ dysfunction.However, the overall severity, such as duration of fever, cardiac dysfunction, IVIG resistance, CAAs, or mortality, follows the order of KDSS > MIS-C > KD.Non-cardiac organ dysfunction is also frequent in MIS-C and KDSS but rare in KD.Based on the epidemiological, clinical, and immunological differences between MIS-C and KD, Sharma et al. [8] proposed that the two be considered different diseases.Irrespective of the relationships among MIS-C, KDSS, and KD, there is no doubt that MIS-C shares more overlapping characteristics with KDSS than it does with KD.
Figure 2 illustrates the relationships between KD, KDSS, and MIS-C.KD is characterized by KD-like features included in the KD diagnostic criteria and systemic inflammation [21].As an infectious trigger, a broad spectrum of microbes have been identified in patients with KD and are considered to play an important role in the pathogenesis of KD (Figure 2A) [30][31][32].KDSS is diagnosed when shock as organ dysfunction is observed in patients with KD-like features and systemic inflammation.A diagnosis of KDSS does not require evidence of concomitant infections, but several microbes such as Epstein Barr virus, influenza virus, or group A streptococcus have been found in KDSS patients (Figure 2B) [10,33].MIS-C is diagnosed when SARS-CoV-2 is identified in patients with KD-like features, systemic inflammation, and organ dysfunction such as shock (Figure 2C) [30].
Among the KDSS group of nine patients, two were hospitalized during the COVID-19 pandemic.Although both patients presented with severe systemic inflammation and multi-organ dysfunction, there was no evidence of recent SARS-CoV-2 infection in their medical history and microbiological examinations.They were diagnosed with KDSS.If evidence of SARS-CoV-2 infection had been demonstrated in these two KDSS patients, they should have been diagnosed with MIS-C.Similarly, if evidence of SARS-CoV-2 infection could not be demonstrated in patients with suspected MIS-C due to KD-like features and shock, they should have been diagnosed with KDSS.In other words, the most important difference between MIS-C and KDSS is whether SARS-CoV-2 has been identified as an infectious trigger [10].
tients with KD and are considered to play an important role in the pathogenesis of KD (Figure 2A) [30][31][32].KDSS is diagnosed when shock as organ dysfunction is observed in patients with KD-like features and systemic inflammation.A diagnosis of KDSS does not require evidence of concomitant infections, but several microbes such as Epstein Barr virus, influenza virus, or group A streptococcus have been found in KDSS patients (Figure 2B) [10,33].MIS-C is diagnosed when SARS-CoV-2 is identified in patients with KD-like features, systemic inflammation, and organ dysfunction such as shock (Figure 2C) [30].CoV-2 is identified in patients with KD-like features, systemic inflammation, and organ dysfunction such as shock.SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; KD, Kawasaki disease; KDSS, Kawasaki disease shock syndrome; MIS-C, multisystem inflammatory syndrome in children.
Among the KDSS group of nine patients, two were hospitalized during the COVID-19 pandemic.Although both patients presented with severe systemic inflammation and multi-organ dysfunction, there was no evidence of recent SARS-CoV-2 infection in their This relatively small and retrospective study has some limitations, and a prospectively designed large-scale study is needed to validate our findings.The number of patients with KDSS could have been underestimated because KD patients who received vasoactive drugs or whose secondary diagnosis was hypotension were selected and included in the KDSS group.This could explain the relatively low incidence of KDSS and the relatively high severity of KDSS in this study.

Conclusions
All patients diagnosed with MIS-C or KDSS in this study exhibited KD-like features, systemic inflammation, and organ dysfunction.The overall severity of systemic inflammation and organ dysfunction was higher in KDSS patients than in those with MIS-C.MIS-C is diagnosed when SARS-CoV-2 infection is demonstrated in a patient with KD-like features, systemic inflammation, and organ dysfunction such as shock.Otherwise, KDSS is diagnosed.In other words, the fundamental difference between MIS-C and KDSS is whether SARS-CoV-2 has been identified as an infectious trigger.MIS-C shares more overlapping characteristics with KDSS than with KD.Understanding the similarities and differences between MIS-C and KDSS will provide useful clues for studying the pathogenesis and therapeutic strategies of KD-like hyperinflammatory diseases, including MIS-C and KDSS.

Figure 2 .
Figure 2. Relationships between KD, KDSS, and MIS-C.(A) KD is characterized by KD-like features and systemic inflammation.Infectious triggers are expected to play an important role in the pathogenesis of KD. (B) KDSS is diagnosed when shock presenting as organ dysfunction is observed in patients with KD-like features and systemic inflammation.(C)MIS-C is diagnosed when SARS-CoV-2 is identified in patients with KD-like features, systemic inflammation, and organ dysfunction such as shock.SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; KD, Kawasaki disease; KDSS, Kawasaki disease shock syndrome; MIS-C, multisystem inflammatory syndrome in children.

Figure 2 .
Figure 2. Relationships between KD, KDSS, and MIS-C.(A) KD is characterized by KD-like features and systemic inflammation.Infectious triggers are expected to play an important role in the pathogenesis of KD. (B) KDSS is diagnosed when shock presenting as organ dysfunction is observed in patients with KD-like features and systemic inflammation.(C) MIS-C is diagnosed when SARS-CoV-2 is identified in patients with KD-like features, systemic inflammation, and organ dysfunction such as shock.SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; KD, Kawasaki disease; KDSS, Kawasaki disease shock syndrome; MIS-C, multisystem inflammatory syndrome in children.

Table 1 .
Comparison of demographic and clinical characteristics between the two groups.

Table 1 .
Comparison of demographic and clinical characteristics between the two groups.

Table 4 .
Comparison of treatment and outcomes between the two groups.